This invention relates to thiazolidine and pyrrolidine compounds of the general formula ##STR2## wherein Q.sup.1 and Q.sup.2 each is methylene or sulfur, but Q.sup.1 and Q.sup.2 are not sulfur at the same time;
R.sup.A is R.sup.a or R.sup.b ; PA1 R.sup.B and R.sup.C each is R.sup.c ; PA1 W is ##STR3## wherein X, Y and Z each is single bond, ##STR4## Z, m, n, p, q, r, s and t each is 0, 1, 2 or 3; R.sup.1, R.sup.2, R.sup.3, . . . , R.sup.20 and R.sup.21 each is R.sup.d ; PA1 R.sup.A is R.sup.b when W is ##STR5## wherein R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 each is R.sup.d ; PA1 R.sup.a is selected from the group consisting of (i) hydrogen, lower alkyl and lower alkenyl, and (ii) lower alkyl and lower alkenyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, hydroxy, lower alkoxy, halogenolower alkoxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; PA1 R.sup.b is selected from the group consisting of (a) (i) aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl, and (ii) aralkyl, heteroalkyl, aralkenyl and heteroaralkenyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, halogeno-lower alkyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, mercapto acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl, and (iii) carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl and heteroaryloxycarbonyl; (b) (i) phenyl and naphthyl, and (ii) phenyl and naphthyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, halogeno-lower alkyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, aralkyloxy, aryloxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; (c) (i) furyl, thienyl and pyridyl, and (ii) furyl, thienyl and pyridyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, halogeno-lower alkyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, aralkyloxy, aryloxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; PA1 R.sup.c is selected from the group consisting of (a) (i) hydroxy, lower alkoxy and amino, and (ii) lower alkoxy, and amino substituted by at least one substituent selected from the group consisting of lower alkyl, aralkyl, heteroaralkyl, aralkenyl, heteroaralkenyl, hydroxy, lower alkoxy, aralkyloxy, heteroaralkyloxy, aryloxy, heteroaryloxy, acyloxy, aryl, heteroaryl, substituted aralkyl and substituted aryl wherein the substituent is lower alkyl, lower alkoxy, halogen and amino; (b) (i) aryloxy and heteroaryloxy, and (ii) aryloxy and heteroaryloxy substituted by at least one substituent selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, halogen and amino, and ##STR6## R.sup.d is selected from the group consisting of (a) (i) hydrogen, lower alkyl, lower alkenyl, aralkyl, heteroaralkyl, alkanoyl, arylalkanoyl, heteroarylalkanoyl, hydroxy, carboxy, amino, mercapto and sulfo, and (ii) lower alkyl, lower alkenyl, aralkyl, heteroaralkyl, alkanoyl, arylalkanoyl, heteroarylalkanoyl, hydroxy, carboxy, amino, mercapto and sulfo substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, lower alkanoyl, aryl, heteroaryl, acyloxy, aroyl, hydroxy, carboxy, amino, guanidino, mercapto, acylamino, acylmercapto, lower alkoxycarbonyl, sulfo, halogen, nitro, cyano, sulfamoyl, lower alkylaminosulfonyl, lower alkylthio and lower alkylsulfinyl; (b) (i) phenyl and naphthyl, and (ii) phenyl and naphthyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkanoyl, acyloxy, hydroxy, carboxy, amino, halogen, nitro, cyano, acylamino, mercapto, acylmercapto, halogeno-lower alkyl, halogeno-lower alkoxy, lower alkylenedioxy, lower alkoxycarbonyl, sulfo, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; (c) (i) furyl, thienyl and pyridyl, and (ii) furyl, thienyl and pyridyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkanoyl, acyloxy, hydroxy, carboxy, amino, halogen, nitro, cyano, acylamino, mercapto, acylmercapto, halogeno-lower alkyl, halogeno-lower alkoxy, lower alkylenedioxy, lower alkoxycarbonyl, sulfo, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl;
and salts thereof which are useful as agents for therapy or prophylaxis of the diabetic complication because they inhibit strongly aldose reductase, and as antihypertensive agents because they inhibit angiotensin I-converting enzyme.
The compounds [I] of this invention can be prepared by following process.
(i) A compound of the formula [I] is yielded by the reaction of a compound of the formula [II] ##STR7## wherein R.sup.A and R.sup.B may be protected by any suitable groups (e.g., lower alkyl, acyl, aralkyl, aralkyloxy, etc.) when R.sup.A and R.sup.B include reactive groups (e.g., amino, hydroxy, mercapto, hydroxyamino, etc.), with the reactive derivative of carboxylic acid of the formula [III] (e.g., acyl halide, acid anhydride, mixed anhydride, active ester, lactone, etc.) by general methods used in peptide syntheses or amide formation reactions EQU HOOC--W--CO--R.sup.C [III],
wherein W and R.sup.C may be protected by any suitable groups (e.g., lower alkyl, acyl, aralkyl, aralkyloxy, etc.) when W and R.sup.C include reactive groups (e.g., amino, hydroxy, mercapto, hydroxyamino, etc.), followed by removal of protective groups by well-known methods (e.g., hydrolysis, hydrogenolysis, ammonolysis, alcoholysis, etc.).
This procedures of deprotection can be applied in the following methods.
(ii) A compound of the formula [I] is yielded by the reaction of a compound of the formula [II] with the reactive derivative of carboxylic acid of [IV] (e.g., above-mentioned) EQU HOOC--W.sup.1 --L [IV],
wherein W.sup.1 is ##STR8## and may be protected such as (i) above, L is a leaving group (e.g., halogen, alkylsulfonyl, arylsulfonyl, etc.), by the same methods as described in (i) above to produce a compound of the formula [V] ##STR9## and then reaction of a compound of the formula [V] with a compound of the formula [VI] EQU (H)X--W.sup.2 --Y--W.sup.3 --Z--W.sup.4 --CO--R.sup.C [VI],
wherein W.sup.2 is ##STR10## W.sup.3 is ##STR11## W.sup.4 is ##STR12## and W.sup.2, W.sup.3, W.sup.4, X, Y, Z and R.sup.C may be protected such as (i) above, in the presence of proper alkaline and/or organic bases, if necessary, by known methods.
(iii) A compound of the formula [I] is yielded by the reaction of a compound of the formula [II] with the reactive derivative of carboxylic acid of the formula [VII] (e.g., metioned in (i) above) EQU HOOC--W.sup.1 X--W.sup.2 --L [VII]
and then with a compound of the formula [VIII] EQU (H)Y--W.sup.3 --Z--W.sup.4 --CO--R.sup.C [VIII]
by the same method as (ii) above.
(iv) A compound of the formula [I] is yielded by the reaction of a compound of the formula [II] with the reactive derivative of carboxylic acid of the formula [IX] (e.g., mentioned in (i) above EQU HOOC--W.sup.1 --X--W.sup.2 --Y--W.sup.3 --L [IX],
and then with a compound of the formula [X] EQU (H)Z--W.sup.4 --CO--R.sup.C [X]
by the same method as (ii) above.
(v) A compound of the formula [I] is yielded by the reaction of a compound of the formula [II] with the structure derivative of carboxylic acid [XI] (e.g., acyl halide, acid anhydride, mixed anhydride, active ester, lactone, thiolactone, etc.) EQU HOOC--W.sup.1 --X(H) [XI],
and then with a compound of the formula [XII] EQU L--W.sup.2 --Y--W.sup.3 --Z--W.sup.4 --CO--R.sup.C [XII]
by the same method as (ii) above.
(vi) A compound of the formula [I] is yielded by the reaction of a compound of the formula [II] with the reactive derivative of carboxylic acid of the formula [XIII] (e.g., mentioned in (v) above) EQU HOOC--W.sup.1 --X--W.sup.2 --Y(H) [XIII],
and then with a compound of the formula [XIV] EQU L--W.sup.3 --Z--W.sup.4 --CO--R.sup.C [XIV]
by the same method as (ii) above.
(vii) A compound of the formula [I] is yielded by the reaction of a compound of the formula [II] with the reactive derivative of carboxylic acid of the formula [XV] (e.g., mentioned in (v) above) EQU HOOC--W.sup.1 --X--W.sup.2 --Y--W.sup.3 --Z(H) [XV],
and then with a compound of the formula [XVI] EQU L--W.sup.4 --CO--R.sup.C [XVI]
by the same method as (ii) above.
(viii) A compound of the formula [I] is also yielded by converting a compound of the formula [I] prepared by any method above-mentioned by well-known methods (e.g., oxidation, formation of oxime, hydrazone and semicarbazone, addition to double bond, etc.)
The compounds [I] of this invention are effective on preventing or relieving diabetic complications.
In diabetic patients, high levels of hexoses (e.g., glucose, galactose, etc.) in blood lead to the accumulation of sugar alcohols (e.g., sorbitol, galactitol, etc.) in tissues. It is known that this accumulation causes the swelling of cells to induce complications of diabetic cataract, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, etc. [R. Quan-Ma et al., Biochem. Biophys. Res. Comm., 22, 492 (1966)]. For example, R. Gitzelman et al. have presented that cataract is caused by the accumulation of sugar alcohols [Exptl. Eye. Res., 6, 1 (1967)]. A report of Kinoshita et al. has demonstrated that aldose reductase which reduced aldose to the corresponding sugar alcohols was involved in the initiation of these diabetic complications and that effective inhibitors of aldose reductase were useful [Jpn. J. Ophthalmol., 20, 339 (1976)]. On the basis of the above information, aldose reductase inhibition of the compounds [I] of this invention was tested. The results of the examinations demonstrated that these compounds have potent inhibitory activities on aldose reductase, and therefore they are useful as drugs for therapy or prophylaxis of the diabetic complications.
On the other hand, it has been known that a kind of the derivatives of thiazolidine- or pyrrolidinecarboxylic acid have potent inhibitory activity to angiotensin I-converting enzyme, but thiazolidine and pyrrolidine compounds of this invention are novel compounds, and have more potent inhibitory activities to angiotensin I-converting enzyme. Furthermore, the compounds of this invention are prepared by convenient methods, and are superior to the stability.
Thus, the compounds of this invention are useful as therapeutic or prophylactic agents and antihypertensive agents.
The compound of formula [I] can form the conventional salts to be generally used as medicine such as sodium salt, potassium salt, calcium salt, magnesium salt, alminum salt, ammonium salt, diethylamine salt, triethanolamine, etc.
The compounds of formula [I] have the stereoisomers which are within the limit of this invention, because they have one or more asymmetric carbon atoms.
Typical examples are shown below, although this invention is not limited to these examples.